Postmenopausal HIV+ women are at increased risk of fracture and vulnerable to adverse effects of D deficiency, HIV infection and ART-related bone loss on bone strength. The increasing prevalence of HIV-infection on older minority women and the aging of the HIV-infected population make it critical to elucidate the effects of HIV and its treatment on bone health. PUBLIC HEALTH RELEVANCE: Older minority women comprise a growing proportion of HIV-infected adults in the United States. This proposal seeks continued support to study "Osteoporosis in HIV-infected Postmenopausal Women" (R01 AI065200). During the current funding period, we documented lower bone density (BMD), higher prevalence of certain non-vertebral fractures, higher bone turnover, higher rates of bone loss in HIV+ women than HIV- women, and indirect evidence of increased osteoclast numbers particularly in HIV+ women on ritonavir-boosted protease inhibitor (RTV-PI) regimens. In addition, vitamin D insufficiency and deficiency were extremely common, affecting 76% of the subjects and were associated with lower current CD4 counts. In the renewal, we will recruit additional HIV+ subjects in order to have greater power to investigate BMD, biochemical and bone cell differences among different antiretroviral therapy (ART) subgroups. Specifically, we will test the hypotheses that certain ART regimens are associated with higher bone turnover, circulating osteoclast and osteoblast precursors, and rates of bone loss;that repletion of vitamin D in D insufficient and deficient HIV+ postmenopausal women will be associated with a decline in bone turnover and rates of bone loss and may influence indices of immune function;that initiation of ART converts the low bone turnover state of untreated HIV infection to a high turnover state associated with detectable bone loss;and that tenofovir disoproxil fumarate (TDF)-based regimens that include RTV-PIs or efavirenz, a cytochrome P450 inducer, will differentially affect BMD, mineral metabolism, bone cells and turnover. We will test these hypotheses utilizing established state-of-the-art biochemical assays and novel technologies, such as high-resolution peripheral quantitative CT (HR- pQCT) and quantification and characterization of circulating osteoblast and osteoclast precursors, which will permit assessment of bone microarchitecture and remodeling activity without the requirement for a bone biopsy.